We propose to submit a new PPG application to facilitate study of the role of the innate immune system in atherogenesis. Once initiated, atherosclerosis has all the characteristics of a chronic inflammatory disease and each Project Leader of the proposed PPG has contributed importantly to the recognition that immunological mechanisms play a central role in modulating disease progression. In vivo studies and our own data suggest that TLRs, which play critical roles in pathogen recognition, also modify atherosclerosis by mediating inflammatory responses to modified lipoproteins and proatherogenic ligands. We propose to use a combination of in vitro and in vivo approaches to understand the regulation of innate immune responses to relevant pathogens, and their impact on inflammation and atherosclerosis. There is extensive evidence that PPARg and PPARd ligands inhibit inflammatory processes, including TLR-dependent mechanisms, and we will use a combination of molecular, cellular and genomics approaches to understand how they control programs of inflammatory gene expression in macrophages and other cells in the artery. Specifically, we will test the hypothesis that NCoR/SMRT/SUMOylation-dependent pathway plays an important role in vitro and in vivo in mediating the anti-inflammatory and anti-atherogenic effects of PPARg and that PPARd regulates the inflammatory state by control of the concentrations of free and nuclear receptor-bound fractions of the co-repressors BCL-6 and SMRT. The relevance of these observations for atherogenesis will be tested using a variety of unique gene targeted murine models. TLRs of innate immunity sense pathogens, both exogenous and endogenous and induce proinflammatory, proatherogenic responses in macrophages and other cells. Using a variety of unique genetic models, we will determine the coreceptors that pair with TR2 to promote atherosclerosis, the ligands with which they interact, and the molecular and cellular mechanisms responsible. A third focus on innate immunity will be on innate B-1 cells and the IgM natural antibodies (NAbs) they secrete, which appear to target oxidation-specific epitopes as found on OxLDL and apoptotic cells. Using reconstituted mice in which all plasma IgM are NAbs, we will explore their role in atherosclerosis and homeostasis. We will explore the regulation of B-1 cells by TLRs and by nuclear receptors and determine the molecular pathways by which this occurs. In summary, our studies will lead to an increased understanding of the innate network of immune regulation, which could lead to novel therapeutic options to control inflammation and atherosclerosis.